(Taken from the application): Neonatal lupus is currently considered a model of passively acquired autoimmunity whereby immune abnormalities in the mother (who may have systemic lupus erythematosus, Sjogrens syndrome, or be entirely asymptomatic) lead to the production of antibodies to the SSA/Ro-SSB/La ribonucleoproteins which cross the placenta and presumably injure the developing fetus. The most serious manifestation is cardiac injury which includes varying degrees of atrioventricular (AV) block, most often third degree, and myocarditis. The mortality approaches 20% and the majority of children require lifelong pacing. This application focuses both on the clinical approach to diagnosed congenital heart block (CHB) [interventional study] and the search for an early echocardiographic marker of injury [observational study].
In Specific Aim 1, a randomized double-blind placebo-controlled trial will examine the effect of daily oral dexamethasone (4 mg) on the outcome of CHB. The rationale rests on the hypothesis that CHB is the consequence of an inflammatory process mediated by maternal anti-Ro/La antibodies. Mothers, irrespective of disease activity but requiring less than 10 mg prednisone/day, identified before 30 weeks of gestation to be carrying a fetus with CHB, will be randomized to receive dexamethasone or placebo (50 patients per arm) for a minimum of 6 weeks. Primary outcome measures include neonatal ventricular rate and ejection fraction at birth, and presence or absence of abnormal fluid collection as assessed on the final fetal echocardiogram before delivery. Secondary outcome measures include the degree of block at birth, gestational age, birth weight, and cardiothoracic ratio.
In Specific Aim 2, we will attempt to identify the earliest noninvasive echocardiographic marker of AV nodal dysfunction and/or myocardial injury. At present it is not known whether injury to the AV node progresses through stages with the final outcome being fibrosis of the node and irreversible third degree block. It has been proposed that global inflammation of the working myocardium and surrounding pericardium may precede or accompany AV nodal injury. One hundred pregnant women considered at high risk for having a child with CHB, as defined by presence of Ro/La antibodies documented prior to pregnancy (regardless of whether or not they have had a previous child with neonatal lupus), will be followed by weekly echocardiograms from 16 weeks of gestation, with special attention to prolongation of the mechanical PR interval and/or development of myocardial dysfunction. Mothers whose fetuses develop 1st, 2nd or 3rd degree block will then be randomized to receive either dexamethasone or placebo as part of Specific Aim 1. The importance of this second aim is twofold: first, it will identify whether the subclinical incidence of tissue injury exceeds overt injury manifest as advanced AV dissociation; and second, it will provide the best chance for reversibility of block given identification of early lesions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046265-03
Application #
6534486
Study Section
Special Emphasis Panel (ZAR1-TLB-B (M1))
Program Officer
Serrate-Sztein, Susana
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$393,292
Indirect Cost
Name
Hospital for Joint Diseases Ortho Institute
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10003
Phoon, Colin K L; Kim, Mimi Y; Buyon, Jill P et al. (2012) Finding the ""PR-fect"" solution: what is the best tool to measure fetal cardiac PR intervals for the detection and possible treatment of early conduction disease? Congenit Heart Dis 7:349-60
Izmirly, Peter M; Kim, Mimi Y; Llanos, Carolina et al. (2010) Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis 69:1827-30
Friedman, Deborah M; Kim, Mimi Y; Copel, Joshua A et al. (2009) Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study. Am J Cardiol 103:1102-6
Buyon, J P; Clancy, R M; Friedman, D M (2009) Autoimmune associated congenital heart block: integration of clinical and research clues in the management of the maternal / foetal dyad at risk. J Intern Med 265:653-62
Strandberg, L; Winqvist, O; Sonesson, S-E et al. (2008) Antibodies to amino acid 200-239 (p200) of Ro52 as serological markers for the risk of developing congenital heart block. Clin Exp Immunol 154:30-7
Friedman, Deborah M; Kim, Mimi Y; Copel, Joshua A et al. (2008) Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study. Circulation 117:485-93
Friedman, Deborah M; Rupel, Ann; Buyon, Jill P (2007) Epidemiology, etiology, detection, and treatment of autoantibody-associated congenital heart block in neonatal lupus. Curr Rheumatol Rep 9:101-8
Izmirly, Peter M; Rivera, Tania L; Buyon, Jill P (2007) Neonatal lupus syndromes. Rheum Dis Clin North Am 33:267-85, vi
Stea, Eleni A; Routsias, John G; Clancy, Robert M et al. (2006) Anti-La/SSB antiidiotypic antibodies in maternal serum: a marker of low risk for neonatal lupus in an offspring. Arthritis Rheum 54:2228-34
Clancy, Robert M; Buyon, Jill P; Ikeda, Keigo et al. (2005) Maternal antibody responses to the 52-kd SSA/RO p200 peptide and the development of fetal conduction defects. Arthritis Rheum 52:3079-86

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